Certain aminopropylidenebenzo(5,6)cyclohepta(1,2-d)thiazoles



United States Patent 3,442,903 CERTAIN AMINOPROPYLIDENEBENZO[5,6]CYCLOHEPTA[l,2-d]THIAZOLES Eugene E. Galantay, Morristown, N.J.,assignor to Sandoz Inc., Hanover, NJ.

No Drawing. Continuation-impart of application Ser. N 0. 610,780, Jan.23, 1967. This application Aug. 30, 1967, Ser. No. 664,313

Int. Cl. C07d 91/42 US. Cl. 260-302 Claims ABSTRACT OF THE DISCLOSUREThe compounds are of the class of 4-(3-monoanddialkylaminopropylidene)-2-lower alkyl-9,10-dihydro 4H-benzo[5,6]cyclohepta[1,2-d]thiazoles which are useful as tranquilizers.The compounds are prepared by thiating a 2-lower alkyl-9,10-dihydro-4H-benzo [5,6] cyclohepta[ 1,2- d]oxazol-4-one, treating theresulting benzocycloheptathiazol-4-one with a metallo dialkylaminopropylhalide Grignard reagent and dehydrating the carbinol resulting from thehydrolysis of the Grignard adduct to obtain the corresponding 4 (3dialkylaminopropylidene)-2-lower alkyl 9,10 dihydro4H-benzo[5,6]cyclohepta[1,2-d] thiazole, which may then be N-dealkylatedto the corresponding 3 monoalkylaminopropylidene-containing analog.

This application is a continuation-in-part of copending applicationSerial No. 610,780, filed Jan. 23, 1967.

This invention relates to tricyclic compounds. In particular, theinvention pertains to benzocycloheptathiazoles and methods for preparingthe same. The invention also relates to intermediates which are usefulin preparing the above compounds and processes for preparing saidintermediates.

The benzocycloheptathiazoles of the present invention may be representedstructurally as follows:

OHCHzOHzN wherein The compounds of structural Formula I wherein R islower alkyl, i.e. compounds Ia, are prepared by treating a 2-loweralkyl-9, l0-dihydro-4H-benzo[5 ,6] cyclohepta[ 1,2- d]oXaz0l-4-one withan alkali hydrosulfide to form the corresponding 2-loweralkyl-9,l0-dihydro-4H-benzo[5,6] cyclohepta[l,2-d]thiazol-4-one,treating the latter with a metallo dialkylaminopropyl halide Grignardreagent, hydrolyzing the resulting Grignard adduct to form thecorresponding 2-lower alkyl 4hydroXy-4-(3-dialkylaminopropyl)-9,lO-dihydro 4H benzo[5,6]cyclohepta[1,2-d]

thiazole and then dehydrating the latter. This process may beillustrated as follows:

R HP

0 S R R X l I X l N Step1 N A 0 II III (1) Grignard Reagent (2)Hydrolysis Step 2 /lower alkyl H O 0 Hz C Hg 0 HzN Dehydration Step 3lower alkyl GHCHzCHzN wherein X, R, R and R" are as previously defined.

In Step I of the process, the benzocycloheptaoxazol-4- one (II) isconverted to the benzocycloheptathiazol-4-one (III) by treatment with asulfur containing reagent (thiating agent) capable of replacing a ringoxygen atom with a sulfur atom. The preferred reagents for this purposeare the alkalihydrosulfides, particularly, the alkali-metalhydrosulfides, e.g., soduim hydrosulfide and potassium hydrosulfide.However, other thiating agents, such as phosphorus pentasulfide can alsobe used. The conversion is conveniently efl ected in an inert polarorganic solvent, e.g., dimethylacetamide, diethylacetamide,dimethylformamide, pyridine, quinoline and sulfolane, and preferably atroom temperature (20-25 (3.), although temperatures between 10 and C.may be utilized.

In Step 2 of the process the tricyclic ketone (III) is condensed with ametallo dialkylaminopropyl halide Grignard reagent and the resultingGrignard adduct then hydrolyzed to form the corresponding carbinol (IV).The preparation of the Grignard reagent, the condensation thereof withthe tricyclic ketone and subsequent hydroly sis of the resultingGrignard adduct are all carried out in the same manner as has previouslybeen described in the prior art for the preparation of thedibenzocycloheptene type tricyclic compounds. Thus, the metallodialkylaminopropyl halides may be prepared by the reaction of anappropriate metal with an ethereal solution of the dialkylaminopropylhalide. The preferred Grignard reagent is a dialkylaminopropylmagnesiumhalide, e.g., dimethylaminopropylmagnesium chloride. Similarly,condensation of the Grignard reagent with the tricyclic ketone isreadily effected in an inert organic solvent, e.g., absolute diethylether, benzene and tetrahydrofuran. After the condensation has beeneffected, the Grignard adduct (condensate product) is hydrolyticallydecomposed under practically neutral conditions, e.g., by hydrolysis inaqueous am- Compounds I have a double bond linking the monoor moniumchloride solution. dialkylamino-propylidene moiety to the 4-position ofthe Dehydration of the carbinol (IV) to the correspondtricyclic system.Hence, compounds I exist as geametric ing derivative (Ia), as indicatedby Step 3, is likewise carisomers, i.e. in cis and trans forms.Compounds IV lack ried out in similar manner as that described in theprior 5 the double bond and therefore do not exist as geometrical artfor the preparation of propylidene derivatives of diisomers; but ondehydration (Step 3), a compound IV benzocycloheptene from theircorresponding carbinols. yields the corresponding compounds Ia as amixture of Thus, the dehydration step may be effected by heatinggeometric isomers. The mixture of isomers can be used diwith alcoholichydrogen chloride. However, the numerous rectly as starting material forStep 4 (the N-dealkylation) other reagents conventionally used fordehydrating similar or separation of isomers can be carried out and amatecarbinols of the dibenzocycloheptene type, e.g., phosphorus rialrich in one isomer used in Step 4 to yield a compound oxychloride,sulfuric acid and the like, may also be em- Ib having a correspondingisomeric make-up. The geoployed. Suitable inert organic solvents for usewith dehymetric isomers or compounds I can be separated by condratingagents include ethanol, glacial acetic acid and ventional means, e.g.,by countercurrent distribution or xylene. by fractional crystallizationof their salts, e.g., their acid Compounds I wherein R is hydrogen, i.e.compounds fumarates, and are included in this invention. Ib, areprepared by N-dealkylation of the corresponding In compounds I wherein Ris other than hydrogen, the compound Ia according to the followingprocedure, i.e. 9-carbon atom of the tricyclic system is an asymmetricreaction scheme B, wherein R, R", R" and X are as decarbon atom. Hence,a compound I, wherein R" is phenyl fined above: can exist as a racemateor in an optically active form. The

N-dealkyla'bion s R 2 Step \h N R cu N CH /lower alkyl (Inc-H2 2 I CH2 21b a In reaction scheme B the N-dealkylation (Step 4) of racemic form aswell as the optical antipodes (enantiomcompound Ia, i.e. a4-(3-dialkylaminopropylidene)-2-l0wers) are within the scope of thisinvention. Resolution of er alkyl9,l0,dihydro-4H-benzo[5,6]cyclohepta1[1,2-d] a racemate of a compound Ican be effected by conventhiazole, to the corresponding compound Ib,i.e. a 4-(3- tional means, e.g., the use of optically active acids. Inmonoalkylaminopropylidene)-2-lower alkyl-9,10-dihydrosome cases greaterpharmacological activity or other bene-4H-benzo[5,6]cycloheptal[l,2-d]thiazole may be accomficial attributesmay be found with respect to a particular plished by conventional means.It is preferred to accomgeometric and/ or optical isomer, and in suchinstances adplish the N-dealkylation by first reacting the compound Iaministration of such isomer may be preferred.

with a lower linear alkyl chloroformate or chlorocarbon- 40 Thecompounds of Formula I are useful because they ate, e.g., having from 1to 6 carbon atoms in the alkylpossess pharmacological activity inanimals. In particular, moiety, such as ethyl, by heating, e.g., at from80 to 200 such compounds possess tranquilizing activity and can be 0, ina suitable solvent, e.g., toluene, to form the correused aspsychotherapeutic agents in the same manner as sponding carbamate esterintermediate (compound Va), chlorpro az kIlOWIl p y peutic dru Thuswhich is then hydrolyzed and decarboxylated by heating, the Compounds,in either their free base form in the e.g., 90 to 180 C., in a stronglybasic medium, e.g., in a form of acid addition salts, e.g.,hydrochloride, hydrosolution of 5 to 15 wt. percent potassium or sodiumhybromide, Sulfate, P p Oxalate, acetate, Citrate, droxide in n-butanol,to form the corresponding compound Irate, P-tolllenesulfonate and thelike, y be admixed with 1b, If d i d, von Braun N-dealkylation procedurecan conventional pharmaceutical carriers or diluents and adb employed fStep 4, e g b fi converting a ministered internally in the same manneras chlorpromapound I to i cyan -derivative (compound v by zine. Thedaily dosage administered is likewise of the same tacting a compound Inwith cyanogen bromide in a suitable Order as that for Chlorpromaline andpp p dosage solvent, e.g., absolute benzene, at 4 to 40 C., and thenforms can be P p accordingly decomposing the cyano-derivative byheating, e.g., at 100 The Compounds of Formula I 3150 P058655antihistato 200 C., preferably refluxing, with an aqueous mineral mimic,e f f i antieholinergic, anti-inflammatory, acid, e.g., hydrochloricacid (5 to 10 wt. percent), prefer- 50 and analgeslc actlvltyably in asuitable solvent, e.g., glacial acetic acid. intermediate Compounds ofFormula III 0 Th intermediates i the N d lk 1 i (step 4 may hibitpharmacological activity in animals. In particular, he representedstructurally as follows (wherein X, R, R Such compounds Possesstfaflquilizing and anti-inflammaand R" are as defined above): toryactivity. For such uses the compounds may be admixed with conventionalpharmaceutical carriers or diluents and administered internally in theform of tablets,

R" capsules, elixirs, solutions or suspensions. The dosage administeredwill, of course, vary depending upon the com- X S Ya pound employed,mode of administration and treatment /R desired. However, in general,satisfactory results are obg 0 Wye an 1 tained when administered at adaily dosage of from about v 5 milli rams er kilo r of bod ht t b t 50CCh9CH2l\\ I g p am y weig o a ou- R milllgrams per kilogram of bodyweight preferably given in divided doses 2 to 4 times a day or insustained release X 8 form. For the larger mammals as well as thesmaller do- 2/3 mestic mammals, dosage forms suitable for internal ad-GEN ministration comprise from about 100 milligrams to about Va 500milligrams of the compound admixed with a solid or R" liquidpharmaceutical carrier or diluent. A. representative formulation is atablet (prepared by standard tabletting procedures) and containing thefollowing ingredients:

Ingredient: Parts by weight 2 methyl9,l-dihydro-4H-benzo[5,6]cyclohepta[ 1,2-d] thiazo-4-one 50 Tragacanth 2Lactose 39.5 Corn Starch Talcum 3 Magnesium stearate 0.5

follows:

alkanoylating agent strong acid wherein X, R and R are previouslydefined.

The nitrosation is conveniently effected in conventional manneremploying an appropriate inert organic solvent, e.g., benzene, tolueneand diethyl ether, and a nitrite, preferably a lower alkyl nitrite,e.g., ethyl nitrite and butyl nitrite. Preferably the reaction iscarried out at room temperature (20 C.) or below and in the presence ofa strong anhydrous acid or base, such as hydrochloric acid or sodiummethoxide, respectively. The 6,7,8,9-tetrahydro-5H-benzocyclohepten-S-ones employed in the above process are either knownand can be prepared as described in the literature or they can beprepared from available materials in analogous manner to that describedin the literature for the preparation of the known compounds.

The 6-isonitroso-6,7,8,9-tetrahydro-5H-benzocyclohepten-S-one isconverted to the benzocycloheptaoxazol-4-one by treatment with anappropriate alkanolylating agent in the presence of a strong acid.Suitable alkanolylating agents include the lower alkanoic acids, e.g.,acetic acid, propionic acid and butyric acid, the corresponding acidanhydrides thereof, e.g., acetic anhydride, propionic anhydride andbutyric anhydride, mixtures of lower alkanoic acids and theircorresponding anhydrides, e.g., acetic acid and acetic anhydride,propionic acid and propionic anhydride and butyric acid and butyricanhydride, lower alkanoyl halides, e.g., acetyl chloride, propionylchloride and butyryl chloride, and mixtures of alkanoyl halides with thecorresponding alkanoic acids and/or anhydrides such as mentioned above.The strong acid employed is desirably a mineral acid, preferably ahydrohalic acid, e.g., hydrochloric acid. The strong acid should beemployed in an amount such that the reaction mixture is strongly acidic.Desirably, the reaction is carried out in the presence of at least 2moles of strong acid per mole of the isonitroso compound. Preferablyfrom 2.5 to 3 moles of strong acid per mole of isonitroso compound areemployed. It is further desirable that the acidity of the reactionmixture is such that an aliquot portion thereof when diluted with water(1: 10) gives a pH of not higher than 2 and preferably is in the rangeof from 0.5 to 1.5. The reaction can be carried out in an inert solventif desired. However, the use of a solvent is not necessary since' anexcess of the alkanoylating agent can be employed for this purpose. If asolvent is employed, the choice thereof is not critical and any inertorganic solvent conventionally used with alkanoylating agents of thetype mentioned above can be employed. Similarly, temperature at whichthe reaction is effected is not critical. In general, it is desirable tocarry out the reaction at an elevated temperature of from about 60 toabout 150 C. Preferably, the reaction is carried out at a temperature offrom C. to about C. In most instances, the resulting product separatesas a solid, when the reaction mixture is poured over ice or diluted withwater, and can be recovered by filtration and further purified bycrystallization in conventional manner. When the product separates as anoil, it can be readily extracted with a suitable solvent, e.g., benzene,and further purified by conventional techniques.

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention.

Example 1.-4 (3-dimethylaminopropylidene)-2-methyl- 9,10dihydro-4H-benzo[5,6]cyclohepta[ l,2-d]thiazole (mixture of cis andtrans) I CHCHzCHzN(CHa)2 Step A. Preparation of6-isonitroso-6,7,8,9-tetrahydro- SH-benzocyclohepten-S-one.To a solutionof 50 g. of 6,7,8,9-tetrahydro-5H-benzocyclohepten-S-one in 210 ml. of0.35 N absolute ethereal hydrochloric acid is added, over a period of 15minutes, 32.2 g. of n-butyl nitrite while maintaining the temperature ofthe reaction mixture between 1520 C. (by external cooling). Aftercrystallization commences petroleum ether is added and the resultingcrystalline material filtered off and washed with petroleum ether toobtain 6-isonitroso-6,7,8,9-tetrahydro- SH-benzocyclohepten-5-one, M.P.l39141 C.

Step B. Preparation of 2-methyl-9,10-dihydro-4H-benzo 5 ,6] cyclohepta 1,2-d] oxazol-4-one.-Hydro gen chloride gas is passed through a mixtureof 45 m1. of glacial acetic acid and 7.8 ml. of acetic anhydride for 15minutes while maintaining the temperature of the mixture at 100 C.Thereafter 2.997 g. of 6-isonitroso-6,7,8,9-tetrahydro-5H-benzocyclohepten-S-one is immediately added while continuing thepassage of hydrogen chloride gas through the mixture and maintaining thereaction temperature at 100 C. during the addition of the ketone and foran additional 15 minutes thereafter. The resulting mixture is thenpoured over ice containing 45 g. of sodium carbonate. The resultingsolids are then recovered by filtration, washed first with water andthen with small amounts of ethyl acetate and then dried to obtain2-methyl-9,l0- dihydro 4H benzo[5,6]cyclohepta[1,2-d]oxazol-4-one, M.P.174-176 C.

Step C. Preparation of 2-methyl-9,l0-dihydro-4H-benzo[5,6]cyclohepta[l,2 d]thiazol-4-one.Hydrogen sulfide gas is passedthrough a suspension of 30.0 g. of potassium tertiary butoxide in 300ml. of dry dimethylformamide. While continuing the introduction ofhydrogen sulfide gas, the resulting suspension is cooled to 5 C. andthen 15 g. of 2-methyl-9,lO-dihydro-4H-benzo[5,6]cyclohepta[1,2-d]oXazol-4-one is added and the resulting mixture stirredfor 30 minutes at 25 C. and then poured over 400 g. of ice. Theresulting mixture is then carefully acidified to pH 4 with concentratedhydrochloric acid. The acidified mixture is filtered and the filtrateextracted twice with ml. (each) of benzene. The com bined benzeneextracts are then washed with 60 ml. of water, dried over magnesiumsulfate and evaporated. The residue is added to 30 ml. of diethyl etherand the resulting solids filtered off to obtain2-methyl-9,l0-dihydro-4H- benzo[5,6]cyclohep-ta[1,2-d]thiazol 4 one,M.P. 138- Step D. Preparation of 4-(B-dimethylaminopropyl)-4-hydroxy-Z-methyl 9,10 dihydro 4H benzo[5,6]cyclohepta[1,2-d]thiazole.Toa Grignard mixture, prepared in conventional manner by reacting 1.6 g.of magnesium with 8.2 g. of 3-dimethylaminopropyl chloride in 40 ml. oftetrahydrofuran at C., is added 5.705 g. of 2-methyl- 9,10-dihydro 4Hbenzo[5,6]cyclohepta[1,2 dJthiazol- 4-one. The resulting mixture ismaintained at 0 C. for 30 minutes and then 50 ml. of a saturatedammonium chloride solution is added. The organic layer is separated andthe aqueous phase repeatedly extracted with diethyl ether. The combinedether extracts are dried over sodium sulfate and evaporated to obtain4-(3-dimethylaminopropyl)-4-hydroxy 2 methyl 9,10 dihydro-4H-benzo[5,6]cyclohepta[1,2-d]thiazole as a viscous oil.

Step B. Preparation of 4 (3 dimethylaminopropylidene) 2 methyl 9,10dihydro-4H-benzo[5,6]cycloheptal[1,2-d]thiazole.The product obtained inStep D is refluxed for 30 minutes with 100 ml. of 4.4 N ethanolichydrochloric acid and the resulting mixture evaporated to dryness. Theresidue is dissolved in 100 ml. of water and the resulting mixtureWashed several times with ethyl acetate to remove any by-products. Theaqueous phase is then made basic (pH 12) by the addition of 5 N sodiumhydroxide solution and extracted three times with 50 ml. (each) ofmethylene chloride. The combined methylene chloride extracts are driedover sodium sulfate and evaporated. The resulting oil is distilled at0.2 mm. pressure and 150-180 C. bath temperature to obtain4-(3-dimethylaminopropylidene)-2-methyl 9,10 dihydro-4H-benzo[5,6]cyclohepta[1,2-d]thiazole as a mixture of cis and trans isomers.

NMR spectrum (60 megahertz, CDCl solution). Vinyl protons: tripletscentered at 351 and 392 cps.

Example 2.2-methyl 4 (3-methylarninopropylidene)- 9,10 dihydro 4Hbenzo[5,6]cyclohepta[1,2-d]thizole (mixture of cis and trans)HCHzCHzIL-CH;

A mixture of 8.036 g. of 4-(3-dimethylaminopropylidene) 2 methyl 9,10dihydro-4H-benzo[5,6]cyclohepta[l,2 d]thiazole (cis and trans isomermixture, obtained as described in Example 1); 4.82 g. of ethylchlorocarbonate and 40 ml. of toluene is refluxed for 24 hours. Thesolution is cooled to room temperature and any unchanged startingmaterial is removed by subsequent extraction with ml. portions of 2 Nhydrochloric acid. The toluene solution is then washed with water, driedover sodium sulfate and evaporated to obtain the intermediate, i.e.4-(3-carbethoxy-3-methylaminopropylidene)- 2methyl-9,10-dihydro 4Hbenzo[5,6]cyclohepta[l,2-d] thiazole as a residue. The mass ofintermediate so obtained is heated under reflux for 18 hours, under anitrogen atmosphere, with a mixture of 6.7 g. of potassium hydroxide and65 ml. of n-butanol. After vacuum evaporation to 5 g., the residue istaken up in 80 ml. of benzene and 80 ml. of water and the benzene layeris washed several times with water; then, the benzene layer is extractedsix times with 20 ml. of 2 N hydrochloric acid. This acid aqueoussolution is made strongly basic (pHlZ to 14) by the addition ofpotassium hydroxide and exhaustively extracted with methylene chloride.The dried methylene chloride solution is evaporated to obtain theproduct as an oil, which is then purified by vacuum distillation (130 C.bath temperature, 0.001 mm. pressure).

The product is a mixture of trans and cis isomers of the title compound,which is characterized by its NMR spectrum (60 megahertz, CDCl solution,tetramethylsilane as internal standard); trans; vinyl proton; tripletcentered at 55.81 p.p.m.; cis; vinyl proton; triplet centered at 66.54p.p.m.

Example 3.2-methyl 4 (3-methylaminopropylidene) 9,10 dihydro 4Hbenzo[5,6]cyclohepta[1,2-d]th1- azole (mixture of cis and trans;alternative process) Step A. Preparation of4-(3-cyano-3-methy1aminopropylidene) 2 methyl 9,10 dihydro 4H benzo[5,6]cyclohepta[1,2-d]thiazole.A solution of 7.8 g. of cyanogen bromide in 30ml. of absolute benzene is added, dropwise at room temperature, to asolution of 15.0 g. of 4 (3 dimethylaminopropylidene) 2 methyl 9,10-dihydro 4H benzo[5,6]cyclohepta[l,2-d]thiazole in 40 m1. of absolutebenzene, the mixture allowed to stand at 20 C. for 12 hours and thenevaporated under vacuum to dryness to obtain a residue. The residue istriturated with ml. of diethyl ether, the resulting mixture filtered andthe filtrate evaporated to dryness to obtain 4-(3-cyano 3methylaminopropylidene)-2-methyl-9,10- dihydro-4H-benzo [5 ,6 cyclohepta1,2-d] thiazole.

Step B. Preparation of 2-methyl-4-(3-methylaminopropylidene) 9,10dihydro 4H benzo[5,6]cyclohepta [1,2-d]thiazole (mixture of cis andtrans; alternative process).9.2 g. of 4-(3 cyano 3methyl-aminopropylidene) 2 methyl 9,10 dihydro 4H benzo[5,6]cyclohepta[l,2-d]thiazole (obtainable according to the proceduredescribed above in Step A) is mixed with 22 ml. of glacial acetic acid,22 ml. of 11 N hydrochloric acid and 146 ml. of water and the mixtureheated under reflux for 4 hours. The reaction mixture is then evaporatedunder vacuum to obtain a residue. The residue is made basic (to pH 12 to14) with 25% aqueous potassium hydroxide, extracted thrice with 50 ml.portions of benzene, the extracts combined, dried over sodium sulfateand evaporated under vacuum to yield 2-methyl-4-(3-methy1-aminopropylidene) 9,10 dihydro 4H benzo[5,6] cyclohepta[1,2-d]thiazoleas a mixture of cis and trans isomers.

Example 4.4 (3 dimethylaminopropylidene) -2 methyl 9 phenyl 9,10 dihydro4H benzo[5,6] cyclohepta[1,2-d]thiazole (mixture of cis and trans) cacaca m 0:1 2

Step A. Preparation of 6-isonitroso-9-phenyl-6,7,8,9- tetrahydro 5Hibenzocyclohepten 5 one.Following the procedure of Step A of Example 1and employing an equivalent amount of 9 phenyl 6,7,8,9 tetrahydro-5H-benzocyclohepten-S-one in place of the 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one used therein, there is obtained 6 isonitroso 9phenyl 6,7,8,9 tetrahydro 5H benzocyclohepten-S-one, M.P. 176 C.

Step B. Preparation of 2 methyl 9 phenyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta[l,2-d]oxazol 4 one-Following the procedure of StepB of Example 1 and employing an equivalent amount of 6-isonitroso-9-phenyl 6,7,8,9 tetrahydro 5H benzocyclohepten 5 one in place of the 6isonitroso 6,7,8,9 tetrahydro-SH-benzocyclohepten-S-one used thereinthere is obtained 2 methyl 9 phenyl 9,10 dihydro 4H benZo 9[5,6]cyclohepta[1,3-d]oxazol 4 one, M.P. 192 to 193.5 C.

Step C. Preparation of 2-methyl-9-phenyl-9,IO-dihydro- 4H benzo[5,6]cyclohepta[l,2-d] thiazol 4 one.Following the procedure of Step C ofExample 1 and employing an equivalent amount of2-methy1-9-phenyl-9,10-dihydro-4H-benzo [5 ,6] cyclohepta[ 1,2-d]oxazol-4-one in place of the Z-methyl 9,10 dihydro 4-Hbenzo[5,6]cyclohepta[1,2-d]oxazol-4-one used therein, there is obtained9 phenyl 9,10 dihydro 4H benzo[5,6]cyclohepta [l,2-d] thiazol-4-one.

Step D. Preparation of 4-(S-dimethylaminopropyl)-4- hydroxy-2-methyl 9phenyl 9,10 dihydro 4H benzo [5,6]cyclohepta[ l,2-d] thiazole-Followingthe procedure of Step D of Example 1 and employing an equivalent amountof 2 methyl 9 phenyl 9,10 dihydro 4H benzo[5,6]cyclohepta[l,2-d]thiazol4 one in place of the 2 methyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta[l,2-d]thiazol-4-one used therein,. there isobtained 4 (3 dimethylaminopropyl) 4 hydroxy 2 methyl 9 phenyl 9,10dihydro 4H benzo[5,61 )cyclohepta l,2-d1thiazole.

Step B. Preparation of 4 (3 dimethylaminopropylidene) 2 methyl 9 phenyl9,10 dihydro 4H benzo [5,6] cyclohepta[1,2 d]thiazole.-Following theprocedure of Step E of Example 1 and employing an equivalent amount of 4(3 dimethylaminopropyl) 4 hydroxy 2 methyl 9 phenyl 9,10 dihydro 4Hbenzo[5,6] cyclohepta[ l,2-d] thiazole in place of the 4 (3dimethylaminopropyl) 4 hydroxy 2 methyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta[1,2-d]thiazole used therein, there is obtained 4 (3dimethylaminopropylidene) 2 methyl 9 phenyl 9,10 dihydro 4H benzo[5,6]cyclohepta[l,2-d] thiazole as a mixture of cis and trans isomers.

4 (3 dimethylaminopropylidene) 2 methyl 9- phenyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta [l,2-d]thiazole isomers may be converted to thecorre sponding isomers of 2 methyl 4 (3 methylaminopropylidene) 9 phenyl9,10 dihydro 4H benzo [5,6]cyclohepta[1,2-d]diazole by following theprocedures described in Examples 2 and 3.

Example 5.-8 chloro 4 (3 dimethylaminopropylidene) 2 methyl 9,10 dihydro4H benzo[5,6] cyclohepta[ 1,2-d1oxazole (mixture of cis and trans) C 1@Qt CH k 3 Step A. Preparation of l chloro 6,7,8,9 tetrahydro 5Hbenzocyclohepten 5 one.Into a mixture of 222 g. of6,7,8,9-tetrahydro-SH-benzocyclohepten-S- one, 442.4 g. of anhydrousaluminum chloride and 500 ml. of 1,1,2,2-tetrachloroethane, stirred at25 C., there is introduced, over a period of 4 hours, 130 g. ofchlorine. Then the mixture is poured onto a mixture consisting of 4 kg.of ice and 550 ml. of 11 N hydrochloric acid. The organic phase isseparated and the aqueous phase is extracted thrice with 100 ml.portions of chloroform. The organic phases are combined and washed twicewith 200 ml. portions of 2 N hydrochloric acid, washed thrice with 200ml. portions of water, dried over sodium sulfate and evaporated to givean oil, which is then fractionated on a spinning band column to give thefollowing products:

(a) 1 chloro 6,7,8,9 tetrahydro 5H benzocyclohepten-S-one: B.P. 130 to131 C./2.7 mm.; n 175764; oxime, M.P. 136 to 138 c.; and

(b) 3 chloro 6,7,8,9 tetrahydro 5H benzocyclohepten 5 one: B.P. 143 to146 C./2.9 mm.;'M.P. 36 to 40 C.; oxime; M.P. 138 to 142 C.

Step B. Preparation of 1 chloro 6 isonitroso- 6,7,8,9 tetrahydro 5Hbenzocyclohepten 5 one.-- Following the procedure of Step A of Example 1and employing an equivalent amount of 1 chloro 6,7,8,9

tetrahydro 5H benzocyclohepten 5 one in place of the 6,7,8,9 tetrahydro5H benzocyclohepten 5 one used therein, there is obtained l-chloro 6isonitroso- 6,7,8,9 tetrahydro 5H benzocyclohepten 5 one, M.P. 174 to175 C. (from diethyl ether-petroleum ether; 1 1

Step C. Preparation of 8 chloro 2 methyl 9,10 dihydro-4H-benzo[5,6]cyclohepta [1,2-d] oxazol-4-one. Following the procedure of Step B ofExample 1 and employing an equivalent amount of 1 chloro 6 isonitroso-6,7,8,9 tetrahydro 5H benzocyclohepten 5 one in place of the6-isonit-roso-6,7,8,9-tetrahydro-5H-benzocyclohepten-S-one used therein,there is obtained 8-chloro- 2-methyl-9,l0-dihydro 4Hbenzo[5,6]cyclohepta[ l,2-d] oxazol-4-one, M.P. to 126 C.

Step D. Preparation of 8-chloro-2-methyl-9,IO-dihydro- 4H-benzo [5 ,6]cyclohepta 1 ,2-d] thiazol-4 one-Following the procedure of Step C ofExample 1, and employing an equivalent amount of8-chloro-2-methyl-9,l0-dihydro-4H-benzo[5,6]cyclohepta[1,2-d]oxazol-4-one in place of the 2-methyl-9,10-dihydro-4H-benzo[5,6]cyclohepta [1,2-d]oxazo1-4-one used therein, there isobtained 8- chloro-2-me-thyl-9,lO-dihydro 4H benzo[5,6]cyclohepta[1,2-d]thiazol-4-one.

Step E. Preparation of 8-chloro-4-(3-dimethy1aminopropyl) 4 hydroxy 2methyl 9,10 dihydro 4H- benzo[5,6]cyclohepta[1.2-d]thiazole.Followingthe procedure of Step D of Example 1 and employing an equivalent amountof 8-chloro-2-methyl-9,lO-dihydro-4H-benzo[5,6]cyclohepta[1,2-d]thiazol-4-one in place of the 2- methyl 9,10dihydro 4H benzo[5,6]cyclohepta[1,2- d]thiazol-4-one used therein, thereis obtained 8-chloro-4- (3 dimethylaminopropyl) 4 hydroxy 2 methyl 9,10-dihydro-4H-benzo[5,6] cyclohepta[ l,2-d]thiazole.

Step F. Preparation of 8-chl0ro-4-(3-dimethylaminopropylidene( 2 methyl9,10 dihydro 4H benzo[5, 6]cyclohepta[l,2-d]thiazole.-Following theprocedure of Step E of Example 1 and employing an equivalent amount of8-chloro-4-(S-dimethylaminopropyl) 4 hydroxy 2- methyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta[1,2- dJ-thiazole in place of the4-(3-dimethylaminopropyl)-4 hydroxy 2 methyl 9,10 dihydro 4H benzo[5,6]cyclohepta[1,2-d]thiazole used therein, there is obtained8-chloro-4-(3-dimethylaminopropylidene) 2 methyl-9, 10-dihydro-4H-benzo[5 ,6 ]cyclohepta[ l,2-d] thiazole as a mixture of cis and transisomers.

8 chloro 4 (3 dimethyl aminopropylidene) 2- methyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta[1,2- d]thiazole isomers may be converted to thecorresponding isomers of 8-chloro-2-methyl-4-(3-methylaminopropylidene)9,10 dihydro 4H benzo[5,6]cyclohepta[1, 2-d]thiazole by following theprocedures described in Examples 2 and 3.

Similarly, the 3-chloro-6,7,8,9-tetrahydro-5H-benzocyclohepten-S-oncobtained as a co-product in Step A of Example 5 can be used as astarting material for the preparation of6-chl0ro-4-(3-dimethylaminopropylidene)- 2 methyl 9,10 dihydro 4Hbenzo[5,6]cyclohepta [1,2-d]thiazole and subsequently6-chloro-2-methyl-4-(3- methylaminopropylidene) 9,10 dihydro 4H benzo[S,

6]cyclohepta[1,2-d]thiazole, by adapting the procedures described inExample 5.

Following the procedure of Step B of Example 1, but replacing the aceticacid and acetic anhydride with equivalent amounts of propionic acid andpropionic anhydride, 2 ethyl 9,10 dihydro 4H benzo[5,6]cyclohepta[1,2-d] oxazol-4-one is obtained, which can be used as a starting materialfor the preparation of 4-(3-dimethylaminopropylidene) 2 ethyl 9,10dihydro 4H benzo [5,6] cyclohepta[1,2-d]thiazole by adapting theprocedure described in Example 1, which can be used for the preparationof2-ethyl-4-(3-methylaminopropylidene)9,10-dihydro-4H-benzo[5,6]cyclohepta[l,2-d]thiazoleby adapting the procedures described in Examples 2 and 3.

What is claimed is:

1. A compound selected from the group consisting ofbenzocycloheptathiazoles of the formula and the pharmaceuticallyacceptable acid addition salts thereof, wherein R represents loweralkyl;

R represents hydrogen or lower alkyl;

R" represents lower alkyl;

R represents hydrogen or phenyl; and

X represents hydrogen or halogen.

2. A compound of claim 1 wherein R is lower alkyl and remainingsubstituents are as defined in claim 1.

3. 4 (3 dimethylaminopropylidene) 2 methyl 9, 10-dihydro-4H-benzo ,6]cyclohepta 1,2-d] thiazole.

4. A compound of claim 1 wherein R is hydrogen and the remainingsubstituents are as defined in claim 1.

5. 4 (3 methylaminopropylidene) 2 methyl 9,10- dihydro-4H-benzo 5 ,6]cyclohepta[ 1,2-d] thiazole.

6. A compound of the formula R0 )T/ T wherein R represents lower alkyl;

R represents hydrogen or phenyl;

A represents cyano or (lower) alkoxycarbonyl;

B represents lower alkyl; and

X represents hydrogen or halogen.

7. A compound of claim 6 wherein A is cyano and the remainingsubstituents are as defined in claim 6.

8. 4 (3 cyano 3 methylaminopropylidene) 2- methyl-9,10-dihydro-4Hbenzo[5,6] cyclohepta[1,2 d] thiazole.

9. A compound of claim 6 wherein A is (lower) a1- koxycarbonyl and theremaining substituents are as defined in claim 6.

10. 4 (3 carbethoxy 3 methylaminopropylidene)- 2-methyl-9,l0-dihydro-4Hbenzo[5,6] cyclohepta[l,2-d] thiazole.

References Cited UNITED STATES PATENTS 2,942,003 6/1960 Copeland260---302 ALEX MAZEL, Primary Examiner.

R. J. GALLAGHER, Assistant Examiner.

US. Cl. X.R.

